This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Obesity induced insulin resistance and cardiac dysfunctions are well documented. Recent evidence suggests that exceeding the capacity of the endoplasmic reticulum (ER stress) with concomitant activation of the unfolded protein response during obesity contributes to insulin resistance and cardiovascular disease. Our studies show that inhibiting ER stress with chemical chaperones alleviates obesity associated insulin resistance and cardiac contractile dysfunctions in high-fat fed mice. We have also found that obesity associated ER-stress is associated with a concomitant upregulation of protein tyrosine phosphatase 1B (PTP1B). The spatial proximity of PTP1B to the ER membrane suggests a possible cross talk between the ER-stress pathway and the activity of this phosphatase. Inhibition of PTP-1B with siRNA did not alter PTP-1B protein levels or expression levels whereas induction of ER-stress lead to augmentation of PTP-1B indicating that ER-stress may be upstream of PTP1B. Confocal microscopy suggested co-localization of PTP1B and ER-stress proteins when cells were challenged with the ER-stressor tunicamycin. Taken together, attenuating the effects by ER-chaperones or by targeting PTP-1B may represent a potential strategy to treat or prevent obesity associated insulin resistance and cardiac dysfunctions.